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Hepatocyte Nuclear Factor-1Β Regulates Wnt Signaling Through Genome-Wide Competition with Β-Catenin/Lymphoid Enhancer Binding

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Hepatocyte Nuclear Factor-1Β Regulates Wnt Signaling Through Genome-Wide Competition with Β-Catenin/Lymphoid Enhancer Binding Hepatocyte nuclear factor-1β regulates Wnt signaling through genome-wide competition with β-catenin/ lymphoid enhancer binding factor Siu Chiu Chana, Ying Zhangb, Marco Pontoglioc, and Peter Igarashia,1 aDepartment of Medicine, University of Minnesota, Minneapolis, MN 55455; bMinnesota Supercomputing Institute, University of Minnesota, Minneapolis, MN 55455; and cDepartment of Development, Reproduction and Cancer, Institut Cochin, Institut National de la Santé et de la Recherche Médicale U1016/Centre National de la Recherche Scientifique Unité Mixte de Recherche 8104, Université Paris-Descartes, Paris, France Edited by Janet Rossant, Hospital for Sick Children, University of Toronto, Toronto, Canada, and approved October 18, 2019 (received for review June 3, 2019) Hepatocyte nuclear factor-1β (HNF-1β) is a tissue-specific transcrip- specific domain and POU-homeodomain responsible for DNA binding tion factor that is essential for normal kidney development and renal at the AT-rich consensus sequence (5′-GTTAANATTAAC-3′) tubular function. Mutations of HNF-1β produce cystic kidney disease, (7). HNF-1β forms homodimers or heterodimers with HNF-1α a phenotype associated with deregulation of canonical (β-catenin– to regulate gene transcription. HNF-1β can function as a tran- β dependent) Wnt signaling. Here, we show that ablation of HNF-1 scriptional activator or repressor depending on the target gene in mIMCD3 renal epithelial cells produces hyperresponsiveness to and cellular context. In the kidney, HNF-1β regulates a network Wnt ligands and increases expression of Wnt target genes, including of genes involved in kidney development and tubular cell dif- Axin2, Ccdc80,andRnf43. Levels of β-catenin and expression of Wnt β ferentiation and proliferation (8). Several transgenic mouse target genes are also increased in HNF-1 mutant mouse kidneys. β Genome-wide chromatin immunoprecipitation sequencing (ChIP-seq) models, including kidney-specific knockout of HNF-1 and trans- β in wild-type and mutant cells showed that ablation of HNF-1β in- genic expression of dominant-negative HNF-1 , have been gen- creases by 6-fold the number of sites on chromatin that are occupied erated and recapitulate phenotypes seen in humans with HNF1B by β-catenin. Remarkably, 50% of the sites that are occupied by mutations (9, 10). β-catenin in HNF-1β mutant cells colocalize with HNF-1β–occupied Previous studies using genome-wide analysis of HNF-1β binding sites in wild-type cells, indicating widespread reciprocal binding. coupled with RNA-expression profiling have identified the genes DEVELOPMENTAL BIOLOGY We found that the Wnt target genes Ccdc80 and Rnf43 contain a that are directly regulated by HNF-1β in renal epithelial cells (11). composite DNA element comprising a β-catenin/lymphoid enhancer These studies have revealed that HNF-1β plays a central role in binding factor (LEF) site overlapping with an HNF-1β half-site. HNF-1β cystic kidney diseases through the regulation of polycystic kidney and β-catenin/LEF compete for binding to this element, and disease (PKD) genes, such as Pkhd1 and Pkd2.Thisapproachhas β β – thereby HNF-1 inhibits -catenin dependent transcription. Collec- also identified novel roles of HNF-1β in renal cholesterol metab- tively, these studies reveal a mechanism whereby a transcription olism, urinary concentration, and expression of noncoding RNAs factor constrains canonical Wnt signaling through direct inhibition (11–13). More recently, loss of HNF-1β has been shown to induce of β-catenin/LEF chromatin binding. epithelial–mesenchymal transition through dysregulation of the Wnt | transcription | polycystic kidney disease | kidney development | β-catenin Significance epatocyte nuclear factor-1β (HNF-1β) is a homeodomain- Canonical Wnt signaling plays essential roles in cell proliferation, containing transcription factor that regulates tissue-specific differentiation, and survival. Binding of Wnt ligands to their H β gene expression in the kidney, liver, pancreas, and other epithelial receptors results in translocation of -catenin to the nucleus, organs (1). In the adult kidney, HNF-1β is expressed exclusively where it interacts with TCF/LEF transcription factors and acti- vates Wnt target genes. Here, we show that the transcription in epithelial cells composing renal tubules and collecting ducts (2). β β HNF-1β is also expressed in the developing kidney, where it is factor HNF-1 competes with the binding of -catenin/LEF essential for normal development. Ablation of Hnf1b in the de- complexes to DNA. We identify a composite DNA element to which HNF-1β binds and thereby inhibits β-catenin-dependent veloping mouse kidney inhibits branching morphogenesis of the transcription. Genome-wide chromatin immunoprecipitation se- ureteric bud and disrupts nephrogenesis and nephron patterning. quencing strikingly revealed that 50% of β-catenin-occupied In humans, mutations of HNF1B were first described in a rare sites in HNF-1β mutant cells colocalized with HNF-1β-occupied autosomal dominant disease called maturity onset diabetes of the sites in wild-type cells, indicating that reciprocal binding is young type 5 (3). More recently, HNF1B mutations and deletions widespread. These studies reveal a direct transcriptional mech- have been associated with a broad spectrum of kidney abnormal- anism for inhibition of canonical Wnt signaling. ities including congenital anomalies of the kidney and urinary tract, autosomal dominant tubulointerstitial kidney disease (ADTKD), Author contributions: S.C.C. and P.I. designed research; M.P. contributed new reagents/ renal agenesis, renal hypoplasia, multicystic dysplastic kidneys, analytic tools; S.C.C., Y.Z., and P.I. analyzed data; and S.C.C., Y.Z., and P.I. wrote the paper. and glomerulocystic kidney disease (4). Extrarenal diseases The authors declare no competing interest. associated with HNF1B mutations include hyperparathyroid- This article is a PNAS Direct Submission. ism, mental retardation, autism, and gout (5). Genome-wide Published under the PNAS license. association studies have linked polymorphisms in HNF1B to Data deposition: The data reported in this paper have been deposited in the Gene Ex- prostate cancer, chromophobe renal cell carcinoma, and clear pression Omnibus (GEO) database, https://www.ncbi.nlm.nih.gov/geo (accession nos. cell ovarian cancer (6). GSE130164 [RNA-seq datasets] and GSE130164 [ChIP-seq datasets]). HNF-1β and its closely related paralog, hepatocyte nuclear 1To whom correspondence may be addressed. Email: [email protected]. factor-1α (HNF-1α), have a similar structure comprising an This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. amino-terminal (N-terminal) dimerization domain, a carboxy- 1073/pnas.1909452116/-/DCSupplemental. terminal (C-terminal) transactivation domain, and a central POU- First published November 11, 2019. www.pnas.org/cgi/doi/10.1073/pnas.1909452116 PNAS | November 26, 2019 | vol. 116 | no. 48 | 24133–24142 Downloaded by guest on October 1, 2021 EMT transcription factor Twist2, which may underlie renal fibrosis Results in HNF1B-related ADTKD (8). Ablation of HNF-1β Activates Canonical Wnt Signaling In Vitro and In β Pathway analysis of target genes has revealed that HNF-1 Vivo. To test whether HNF-1β plays a role in Wnt signaling, we β regulates intracellular signaling pathways. For example, HNF-1 treated HNF-1β mutant cells with the canonical Wnt ligand Wnt3a constrains cyclic adenosine monophosphate (cAMP)-dependent and measured the effects on β-catenin–dependent gene tran- signaling through transcriptional activation of the phosphodies- scription. We previously used CRISPR-based gene editing to de- terase Pde4c and the polycystin-2 calcium channel that forms lete the first exon of Hnf1b in mIMCD3 renal epithelial cells (8). a complex with the calcium-sensitive adenylate cyclase AC5 (14). Deletion of exon 1 resulted in loss of HNF-1β protein and greatly One of the highest-scoring pathways that emerged from the reduced expression of its known downstream target genes, such as analysis of HNF-1β target genes was Wnt signaling. Wnts are se- Pkhd1. To determine the effects on gene expression, we performed creted glycoproteins that play essential roles in embryonic devel- RNA-seq analysis on Wnt3a-treated HNF-1β mutant cells and opment, stem cell renewal, and cell proliferation, differentiation, compared the global transcriptome profiles with wild-type cells and survival (15). In the canonical Wnt pathway, binding of Wnt ligands to their cell-surface receptors results in β-catenin accu- and untreated cells (Fig. 1A). Under basal conditions, we detected > mulation and translocation to the nucleus, where it interacts with 2,733 genes that showed 2-fold increased or decreased expression β– TCF/LEF transcription factors and activates Wnt target genes in HNF-1 deficient cells compared with wild-type mIMCD3 cells (16). Deregulation of Wnt signaling occurs in diseases such as (SI Appendix,Fig.S1A). Treatment with Wnt3a altered the ex- cancer and PKD (17). However, the role of HNF-1β in the regu- pression of 124 genes in wild-type mIMCD3 cells (SI Appendix, lation of Wnt signaling has not been studied previously. Here, we Table S1), whereas the number of Wnt-responsive genes was in- used next-generation RNA-sequencing (RNA-seq) and chromatin creased 8-fold in HNF-1β–deficient cells (SI Appendix,TableS2). immunoprecipitation-sequencing (ChIP-seq) methods to identify Both the number of genes and the magnitude of changes in gene
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